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Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01105377
First received: April 15, 2010
Last updated: November 9, 2012
Last verified: November 2012
History of Changes
  Purpose

This phase II trial is studying how well giving azacitidine together with entinostat works in treating patients with metastatic colorectal cancer. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may kill more tumor cells


Condition Intervention Phase
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
 Drug: entinostat
Other: pharmacogenomic studies
Drug: azacitidine
Other: laboratory biomarker analysis
 Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Azacitidine and Entinostat in Patients With Metastatic Colorectal Cancer

Resource links provided by NLM:

Drug Information available for: Azacitidine
U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Proportion of confirmed tumor responses defined to be either a CR or PR as measured by RECIST criteria version 1.1 [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated using the approach of Duffy and Santner.


Secondary Outcome Measures:
  • Toxicity as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    These analyses will include tables of maximum adverse events (AEs) that are at least possibly related to treatment, general frequency tables summaries of AEs for events of grade 4 or 5.

  • Progression-free survival [ Time Frame: From the start of treatment to the earliest of the date documentating disease progression or the date of death, assessed up to 3 years ] [ Designated as safety issue: No ]
    Estimated using the method of Kaplan-Meier.


Estimated Enrollment: 82
Study Start Date: April 2010
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (entinostat, azacitidine)
Patients receive azacitidine subcutaneously on days 1-5 and 8-10 and oral entinostat on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 Drug: entinostat
Given orally
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Other: pharmacogenomic studies
Correlative studies
Other Name: Pharmacogenomic Study
Drug: azacitidine
Given SC
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the preliminary efficacy via Response Evaluation Criteria In Solid Tumors (RECIST) response rate of the combination of azacitidine and entinostat in patients with metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. Explore the effects of azacitidine and entinostat on time to progression in patients with metastatic colorectal cancer.

II. To assess the toxicity for combination azacitidine and entinostat therapy.

TERTIARY OBJECTIVES:

I. Evaluate changes in promoter methylation of selected genes from DNA in circulating serum samples.

II. To determine changes in histone deacetylase activity and acetylation of H3 and H4 histones in pre- and post-treatment tumor biopsies.

III. To evaluate correlations between these molecular effects and clinical outcomes (response, time to progression).

IV. To correlate response rates by RECIST criteria versus response rates determined be EASL (change in tumor enhancement).

OUTLINE: This is a multicenter study.

Patients receive azacitidine subcutaneously on days 1-5 and 8-10 and oral entinostat on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood and tumor tissue samples are collected at baseline and periodically during courses 1-3 for DNA methylation, histone deacetylation activity, and acetylation of H3 and H4 histones analysis by PCR, western blot, and RT-PCR assays. Pharmacogenomic studies may also be conducted.

After completion of study therapy, patients are followed up every 3-6 months for up to 3 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed metastatic colorectal cancer
  • Measurable disease
  • Patient has failed ≥ 2 prior chemotherapy regimens
  • Not a candidate for curative resection

  • No CNS metastases within ≤ 2 years

    • Treatment for brain metastasis and whole brain disease that has remained stable for > 3 months allowed
    • Patients who have not been treated with steroid therapy may be allowed
  • ECOG performance status 0-1
  • Life expectancy ≥ 12 weeks
  • Leukocytes ≥ 3,000/mm^3
  • ANC ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • Negative pregnancy test
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • Sensory neuropathy ≤ grade 2 allowed
  • Willing to provide tissue and blood samples
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat, azacitidine, mannitol, or other agents used in the study

  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • NYHA class II-IV symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness and/or social situations that would limit compliance with study requirements
  • No history of severe bleeding without thrombocytopenia
  • No concurrent radiotherapy including palliative treatment
  • Toxicities from prior therapy have resolved to ≤ grade 1
  • More than 4 weeks since prior chemotherapy (> 6 weeks for nitrosoureas or mitomycin C)
  • More than 4 weeks since prior major surgical procedure
  • No prior histone deacetylase inhibitors (including valproic acid) or demethylating agents
  • No concurrent investigational agents
  • No concurrent combination antiretroviral therapy in HIV-positive patients
  • No concurrent investigational or commercial anticancer agents or therapies
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01105377

Locations
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, California
University of Southern California
Los Angeles, California, United States, 90033-0804
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48202
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Metro-Minnesota CCOP
Saint Louis Park, Minnesota, United States, 55416
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, Pennsylvania
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15232
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Nilofer Azad Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01105377     History of Changes
Other Study ID Numbers: NCI-2010-02024, MC084B, N01CM62209, N01CM62205, CDR0000670136
Study First Received: April 15, 2010
Last Updated: November 9, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colonic Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
 Intestinal Diseases
Rectal Diseases
Azacitidine
Histone Deacetylase Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 16, 2013